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Benzodiazepines and the gut

Pegasus

Ex-Bluelighter
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Aug 15, 2006
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There doesn't seem to be much information available on this topic, so I'm hoping someone in ADD can help me out a little here. There seems to be a connection between benzodiazepines and bowel function, hence why chlordiazepoxide is a common treatment for IBS. Is this connection understood? I've tried researching it and am not coming up with much.

The reason I'm wondering about this is because of my recent experience with alprazolam withdrawal. My bowel function was significantly disturbed by the withdrawal, causing me to have urgent, loose stool for around a month. I eventually got tired of this and started taking psyllium husk fiber supplements which greatly helped. I continued the husks for about two months until bout a week ago, I decided to stop and the bowel disruption came back, but not just the bowel issues-- many symptoms of benzo withdrawal came back including blepharospasms, excessive tremors, and other sensations that I only experienced while in withdrawal.

Can anyone explain this correlation? I'm curious just how strong of a role the gut plays in benzodiazepine action and withdrawal. I notice that gut disorders like celiac and Crohn's can cause seizures and withdrawal from any GABAnergic drug seems to cause GI complications. Can anyone tell me anything more?
 
This isn't a scholarly source but fwiw:

GABA receptors for Benzodiazepines and Sleeping Pills are also located in the gut and depress gastrointestinal movement, which can cause constipation. But the continued use of medications that target GABA also increase the level of stress on the body. And in many ways, the connection between stress and the gut may be the most visible brain-gut connection. Chronic stress can result in indigestion, ulcers and a host of uncomfortable symptoms, including colon spasms. This may explain why the gut naturally produces benzodiazepines, to keep the natural state of calm that is necessary for proper functioning.

from http://www.pointofreturn.com/gut_health.html
 
...naturally produces benzodiazepines? What?? Can someone point me to some external source(s) explaining/confirming this?

I have been prescribed a whole host of benzos and GABAergic neuroleptics for GAD and comorbid panic disorder, supposedly have leaky gut syndrome according to a homeopathic health practitioner, have chronic insomnia AND am exposed to chronic stress being that I am employed full time at a mental health facility I.e. Rotating shift work. This information could be of vital interest to my short- and long-term health and vitality (what's left of either, that is :( ).

So fucking glad I decided to browse ADD tonight and you're right, this topic deserves way more attention!

~ Vaya
 
http://biopsychiatry.com/natural-benzos.html

Make of that what you will.

Ashton Manual said:
Digestive problems. Some people have no problems at all with their digestive systems during or after withdrawal, and may even notice that they are enjoying their food more. Others, perhaps more prone constitutionally, may complain of a range of symptoms associated with "irritable bowel syndrome" (IBS). These can include nausea, vomiting, diarrhoea, constipation, abdominal pain, flatulence, gaseous distension and heartburn. Quite a few have found these symptoms so uncomfortable that they have undergone hospital gastrointestinal investigations, but usually no abnormality is found. The symptoms may be partly due to overactivity in the autonomic nervous system, which controls the motility and secretions of the gut and is very reactive to stress, including the stress of benzodiazepine withdrawal. In addition, there are benzodiazepine receptors in the gut. It is not clear what the functions of these receptors are or how they are affected by benzodiazepines or benzodiazepine withdrawal, but alterations in these receptors may play some part in increasing gut irritability.
 
I appreciate that link sekio; I've read The Ashton Manual and understand that it supports what the OP's post suggests. What caught me off guard is the notion that the body produces "natural benzodiazepines" - or am I misunderstanding something I'm reading here? I mean, if this is true, which benzodiazepines does the body produce? Or are we really just talking about receptor location density?

Much love,

~ Vaya
 
Very interesting article. I have never read about the symptoms of IBS, but after reading them I realized it describes my situatio perfectly. Ever since my daughter was born, my wife and I seperated, and I moved three hours away to attend grad school my stress level is through the roof. I wake up the majority of mornings because my stomach physically hurts. It is not heartburn or gas (althouh I do get those), it is a physical pain in my stomach. Sometimes it becomes so bad that I throw up. The other morning I threw up six times between 2 and 8 A.M. and I was not nauseous at all, it was simply from spasms and pain in my stomach. It is getting very bad, and threatens to interfere with graduate school. Benzodiazepenes and opiates are the only medications that have helped thus far. I cannot take the opiates because I do not want to risk addiction, and the same goes for the benzos. I honestly feel kind of trapped with this problem. I generally have pretty bad anxiety right now, I sweat easily and my heart rate can get pretty fast at seemingly mild anxiogenetic situations. If anyone knows of a good solution, I would very much appreciate it.

In my medical pharmacology class we were discussing the parasympathetic nervous system, and I thought that the parasympthetic nervous system actually increased gut motility and digestive functions. Here it seems that people are saying the opposite, that activation of the sympathetic nervous system induced via withdrawl from GABAergic drugs increased gut motility and the digestive system, so much so it was ramped up to an uncomfortable degree. I have never experienced benzodiazepene withdrawl so I cannot comment. Did I just remember the information wrong?
 
I think this gut-brain relationship really needs to be studied more. It amazes me that there is such a focus on creating new drugs rather than understanding the body more in depth. There is a reason that the body responds to certain stresses with diarrhea. Surely it is related how drugs like opioids rid the body of stress and cause constipation (also, prevent colds/ flu). Surely there is a reason why benzodiazepines work well for IBS but also cause the problem in withdrawal. Rather than focusing on creating new drugs to cover up every symptom, the focus needs to be on understanding the complexities of the body and preventing us from hurting ourselves with out bad habits.
 
Thanks for the links guys. I know what the Ashton Manual says, but it essentially bypasses the whole understanding I'm looking for with the term "IBS". IBS isn't really a diagnosis, it's more of a way for a doctor to say they don't know why the problem is happening but agree that there is a problem.

These benzodiazepine receptors in the gut, as well as opioid receptors in the gut and the gut itself, really need to be looked at more. It's like a relatively unexplored frontier down there, it seems.
 
I think this gut-brain relationship really needs to be studied more. It amazes me that there is such a focus on creating new drugs rather than understanding the body more in depth. There is a reason that the body responds to certain stresses with diarrhea. Surely it is related how drugs like opioids rid the body of stress and cause constipation (also, prevent colds/ flu). Surely there is a reason why benzodiazepines work well for IBS but also cause the problem in withdrawal. Rather than focusing on creating new drugs to cover up every symptom, the focus needs to be on understanding the complexities of the body and preventing us from hurting ourselves with out bad habits.

I have the same problem pegasus, whether it be from Opioids or Benzos, my belief is that since these are 2 drugs that the body becomes physically dependent upon, when going through a withdrawal phase you can look at like a cleansing of the body. If you have experienced a colonic, this is exactly how the body evacuates everything the colonic hasnt literally sucked out of you. I guess in some respect you can look at it as your body re adjusting itself to normal functioning, before these drugs were added to the system.

And this OT, but I find it especially strange that when you are in the process of going to get something like coke, or heroin, or whatever your flavor is, that you are on the threshold of literally shitting yourself. Now thats something I would truly like to understand. I can understand the body cleaning it self out, but the need to defecate while in the process of your purchase, that I have never understood
 
I think this gut-brain relationship really needs to be studied more. It amazes me that there is such a focus on creating new drugs rather than understanding the body more in depth. There is a reason that the body responds to certain stresses with diarrhea. Surely it is related how drugs like opioids rid the body of stress and cause constipation (also, prevent colds/ flu). Surely there is a reason why benzodiazepines work well for IBS but also cause the problem in withdrawal. Rather than focusing on creating new drugs to cover up every symptom, the focus needs to be on understanding the complexities of the body and preventing us from hurting ourselves with out bad habits.

Opioids prevent colds and the flu? I have not heard of that. Certainly they can make your perception of being sick drastically different, but as far as I know they have no immuno boosting effect. I think most of these questions have been answered actually, one just needs to look in the appropriate places. For example, opioids cause constipation because of a decrease in gut motility mediated by opioid receptors in the small intestine.
 
I think the reason may bea as simple as the gut developing the classical symptoms of tolerance , dependence, and withdrawal. If there are BZD, 5-HT, opioid etc receptors then I see no reason that e.g. internalization happens and the body's endorphin or GABA or what have you are no longer enough to control gut motility.
 
I think the reason may bea as simple as the gut developing the classical symptoms of tolerance , dependence, and withdrawal. If there are BZD, 5-HT, opioid etc receptors then I see no reason that e.g. internalization happens and the body's endorphin or GABA or what have you are no longer enough to control gut motility.

I would agree. My question though is why benzo withdrawl produces an increase in gut motility. My understanding is that parasympathetic activation (mainly through muscanaric acetycholine neurotransmitters) produces an increase in gut motility. Now, benzo withdrawl will show a marked increase in the ympathetic nervous system (mediated largely by NE in post ganglionic innervations) because of an inability to dampen the nerve signals effectively given the reduction in GABAergic suppression. So the sympathetic nerous system would be in overdrive. The sympathetic innervations in the gut cause a decrease in gut motility. So shouldn't benzo withdrawl actually cause a large decrease in gut motility, i.e. constipation? Somewhere in my chain of events I am getting something wrong, I just don't know which part.
 
I would agree. My question though is why benzo withdrawl produces an increase in gut motility. My understanding is that parasympathetic activation (mainly through muscanaric acetycholine neurotransmitters) produces an increase in gut motility. Now, benzo withdrawl will show a marked increase in the ympathetic nervous system (mediated largely by NE in post ganglionic innervations) because of an inability to dampen the nerve signals effectively given the reduction in GABAergic suppression. So the sympathetic nerous system would be in overdrive. The sympathetic innervations in the gut cause a decrease in gut motility. So shouldn't benzo withdrawl actually cause a large decrease in gut motility, i.e. constipation? Somewhere in my chain of events I am getting something wrong, I just don't know which part.

Here is a good link to learn more about the role of the Parasympathetic Nervous System. If you could re-phrase your question so it is not as confusing (and sometimes mis-spelled ;) ) I'd love to help give you an answer. I love talking about this stuff; I can tell you do, too, which is awesome.

~ vaya
 
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"Now, benzo withdraw[a]l will show a marked increase in the ympathetic nervous system (mediated largely by NE in post ganglionic innervations) because of an inability to dampen the nerve signals effectively given the reduction in GABAergic suppression."

Whilst attempting to answer your question, it is this one particular sentence that I find so confusing. Can you please clarify?

~ vaya

edit: in attempting to re-word just this sentence, even, I'm finding difficulty; I've come up with "Reduced suppression of GABA causes benzo withdrawal to elicit more activity from the SNS due to ineffective disruption of neuronal transduction," but I'm still finding myself tripping up on words. And this is a question within a question. Lol. So, insodoing, I wanted to clarify why I required clarification before I could continue :)
 
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Thanks for the links guys. I know what the Ashton Manual says, but it essentially bypasses the whole understanding I'm looking for with the term "IBS". IBS isn't really a diagnosis, it's more of a way for a doctor to say they don't know why the problem is happening but agree that there is a problem.

These benzodiazepine receptors in the gut, as well as opioid receptors in the gut and the gut itself, really need to be looked at more. It's like a relatively unexplored frontier down there, it seems.

this is a good observation. If some benzos may cause muscle relaxation, it may be inferred that benzos could promote bowel movements. However, if someone has IBS that is stress related, which often seem to go hand in hand (IBS and high stress), then the opposite could occur.
 
well i kno im a little late in this discussion and dont have too much too add that has not ben said but, I do get IBS when coming off benzo's or even when im on them and wake up in the morning its discomforting, until i dose myself. I am a heavy Benzo user, but have not had any long term IBS effects affter being clean from them. I still just get the kicks and shakes every now n then like fast twitches when being still (like in bed).
 
Here is a good link to learn more about the role of the Parasympathetic Nervous System. If you could re-phrase your question so it is not as confusing (and sometimes mis-spelled ;) ) I'd love to help give you an answer. I love talking about this stuff; I can tell you do, too, which is awesome.

~ vaya

Sorry for the less than stellar grammar. Sometimes I write these responses while I am in the middle of work, and my mind works faster than my fingers. I will do my best to clarify my questions in the future. What I meant by the specific question that you quoted was actually pretty simple, but I did a fine job of making it complicated and unreadable. Sorry for that. Let me try again. It is my understanding that benzodiazepene withdrawl will produce effects that resemble an overactive sympathetic nervous system. In the sympathetic nervous system, norepinephrine is the primary neurotransmitter released at post ganglionic neurons that are innervated to the effector target (tissues, organs, etc...) GABA neurons act to inhibit neuronal firing by stabilizing the inactive state of sodium channels, thus making it less likely that an action potential will arise and cause a neuron to fire. This was a long and drawn out way of saying that during beno withdrawl, your GABA neurons will not work as efficiently as they normally would, so there will be less suppression of the sympathetic nervous system, and that causes things like anxiety, increased heart rate, etc...

Now, where I get confused is the effect this has on the gut. I have been taught that the sympathetic nervous system promotes a decrease in gut motility, effectively causing constipation. This is because if you are in a situation that requires flight or fight, your body will devote energy to things more important than digesting food and moving it through your intestines. So, if all of this holds true, wouldn't benzo withdrawl cause constipation, not an overactive digestive system that has you spewing diarrhea every ten minutes? The only thing I can think of is that during withdrawl there is a decrease in digestion, so your food just flies through your intestines undigested and comes out as liquid. To me though, this would be an increase in gut motility, which is the opposite of what I have been taught. I hope that was clear, let me know if I need to give it another try ;-).
 
I appreciate that link sekio; I've read The Ashton Manual and understand that it supports what the OP's post suggests. What caught me off guard is the notion that the body produces "natural benzodiazepines" - or am I misunderstanding something I'm reading here? I mean, if this is true, which benzodiazepines does the body produce? Or are we really just talking about receptor location density?

Much love,

~ Vaya

This question has not been addressed yet, or have I misinterpreted something?

Anyway I became very curious about it myself and found this:

http://www.omsj.org/drugs/Zavala 1997.pdf

Several endogenous ligands for the BDZ receptor have been identified. They include BDZ-type ligands, which can act as mixed-type ligands and porphyrins which bind selectively to the peripheral BDZ-Rs.

This is not copied verbatim because I cannot select the text using my current pdf plugin, but there is also mention of the source: Klotz, 1991.

It would be interesting to see a structure of such a BDZ-like ligand, it is implicit that they are elucidated I assume. Even if I could do it easily right now I need to get some sleep.
 
This might help a little.



Effects of GABA on circular smooth muscle spontaneous activities of rat distal colon
S Bayer, F Crenner, D Aunis, F Angel ,


Purchase
INSERM Unité 338. Groupe de Neurogastroentérologie. Pavillon Poincaré. Hôpital Civil. 67000 Strasbourg, France
Received 23 July 2001; Accepted 1 February 2002. Available online 22 May 2002.

Abstract
GABAergic regulation of intestinal motility through the modulation of non-adrenergic non-cholinergic (NANC) neurons remains poorly understood especially in rat colon where very few studies have been undertaken. Thperefore, the effects of GABA on circular preparations of rat distal colon were investigated using classical organ bath chambers to record spontaneous mechanical activities (SMA). SMA was characterized by the occurrence of rhythmic phasic contractions (type-I) or by spontaneously occurring large contractions superimposed on small rhythmic contractions (type-II). In the presence of atropine and guanethidine (NANC conditions), these large contractions were inhibited by bicuculline, a GABAA-receptor antagonist as well as by TTX, L-NAME and apamin together, or L 732-138, a NK1-receptor antagonist. In NANC conditions, GABA induced a transient monophasic relaxation or a biphasic effect characterized by a relaxation followed by a tonic contraction in both type-I and -II preparations. Both the inhibitory and excitatory effects of GABA were blocked by TTX and L-NAME + apamin; the GABA-induced contraction was also sensitive to L 732-138. The responses to GABA were mimicked by the GABAA-receptor agonist, muscimol, whereas baclofen and CACA, respectively GABAB and GABAC-receptors agonists showed no effect. These results demonstrated that only GABAA-receptors seem to be involved in the regulation of SMA in rat distal colon in NANC conditions. Release of NANC inhibitory transmitter (NO and probably ATP) and NANC excitatory transmitter (maybe substance P) might be involved.

Keywords: GABA; NANC neurons; Smooth muscle; Motility; Colon; Rat



More http://www.frontiersin.org/gastrointestinal_pharmacology/10.3389/fphar.2010.00124/full


summary of above

γ-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the body and hence GABA-mediated neurotransmission regulates many physiological functions, including those in the gastrointestinal (GI) tract. GABA is located throughout the GI tract and is found in enteric nerves as well as in endocrine-like cells, implicating GABA as both a neurotransmitter and an endocrine mediator influencing GI function. GABA mediates its effects via GABA receptors which are either ionotropic GABAA or metabotropic GABAB. The latter which respond to the agonist baclofen have been least characterized, however accumulating data suggest that they play a key role in GI function in health and disease. Like GABA, GABAB receptors have been detected throughout the gut of several species in the enteric nervous system, muscle, epithelial layers as well as on endocrine-like cells. Such widespread distribution of this metabotropic GABA receptor is consistent with its significant modulatory role over intestinal motility, gastric emptying, gastric acid secretion, transient lower esophageal sphincter relaxation and visceral sensation of painful colonic stimuli. More intriguing findings, the mechanisms underlying which have yet to be determined, suggest GABAB receptors inhibit GI carcinogenesis and tumor growth. Therefore, the diversity of GI functions regulated by GABAB receptors makes it a potentially useful target in the treatment of several GI disorders. In light of the development of novel compounds such as peripherally acting GABAB receptor agonists, positive allosteric modulators of the GABAB receptor and GABA producing enteric bacteria, we review and summarize current knowledge on the function of GABAB receptors within the GI tract.



Full article is long but conclusion:


Summary and Conclusions
The diversity of GI functions regulated by GABAB receptors make it a potentially useful target in the treatment of several GI disorders, but may also limit its therapeutic application due to off target side effects, both in the GI tract and centrally. For example GERD patients and healthy volunteers treated with baclofen reported adverse effects of a neurological nature that included drowsiness and dizziness (Lidums et al., 2000; van Herwaarden et al., 2002; Ciccaglione and Marzio, 2003). However, the development of peripherally acting compounds such as lesogaberan, which by virtue of its affinity for GABA carriers (Lehmann et al., 2009) limits its effects at central GABAB receptors, may well overcome the disadvantages associated with traditional GABAB agonists. Lesogaberan, like baclofen, displays efficacy in the treatment of GERD (Boeckxstaens et al., 2010a,b), but has yet to be tested in other GI disorders where targeting peripheral GABAB receptors could also be therapeutically useful, i.e., in motility disorders. Furthermore, over the last several years a number of positive allosteric modulators of the GABAB receptor have been developed (Urwyler et al., 2001, 2003; Malherbe et al., 2008). One of which, CGP7930, reduces the visceral pain response induced by CRD (Brusberg et al., 2009) and may therefore be therapeutically useful in the treatment of functional bowel disorders such as irritable bowel syndrome where visceral pain is a predominant and debilitating symptom. These modulators offer advantages over traditional GABAB agonists, such as baclofen, as their actions occur following enhancement of endogenous GABA release or transmission, thereby limiting the side-effects that are normally associated with traditional agonist treatment. More novel strategies for delivering GABA to the GI tract in the form of engineered bacteria, such as GAD transfected Bifidobacterium longum (Park et al., 2005), or the development of GABA containing functional foods (Minervini et al., 2009) are in their infancy, but may offer potential in treating GI conditions that are GABA or GABAB receptor-sensitive.
 
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